Abstract
Background
Filamin A (FLNA)–related disease is an emerging heritable aortopathy; however, evidence guiding surgical thresholds and the extent of aortic replacement remains limited.
Case Summary
A 34-year-old woman had progressive postpartum dyspnea and severe aortic regurgitation from right coronary cusp bending, fenestration, and prolapse. Imaging showed a 53-mm ascending aortic aneurysm, and genetic testing identified a pathogenic FLNA variant. She underwent bioprosthetic aortic root and total arch replacement. Histopathology showed diffuse medial degeneration in the aortic root, ascending aorta, and aortic arch, along with severe right coronary cusp degeneration.
Discussion
Prior reports describe aortic rupture at modest diameters and dilation of unreplaced segments. This case demonstrates histopathologic pan-aortic involvement despite focal imaging, and it supports considering extended replacement once standard surgical criteria are met in selected patients.
Take-Home Messages
FLNA aortopathy warrants pan-aortic surveillance. When technically and physiologically feasible, extended graft replacement may be considered in selected patients.
Key words: aortic regurgitation, Bentall procedure, Filamin A, heritable thoracic aortic disease, histopathology, total arch replacement
Visual Summary
Visual Summary.
Extended Aortic Replacement for FLNA-Related Aortopathy
This visual summary illustrates the management of a 34-year-old woman with FLNA-related aortopathy presenting with severe aortic regurgitation and an ascending aortic aneurysm. The patient underwent successful extended aortic root and total arch replacement. Histopathologic analysis confirmed pan-aortic medial degeneration with diffuse elastic fiber fragmentation extending from the aortic root to the distal arch, supporting the strategy of extended prophylactic replacement in patients with FLNA-related aortopathy. AR = aortic regurgitation; RCC = right coronary cusp.
History of Presentation
A 34-year-old woman presented with a 5-year history of progressive dyspnea that began in the postpartum period after a cesarean delivery for pregnancy-induced hypertension. On examination, a new diastolic murmur prompted further evaluation. Her height was 1.51 m and her weight was 43 kg.
Take-Home Messages
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In young patients with ascending aortic dilation, heritable aortopathies including FLNA-related disease should be considered.
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In FLNA-related aortopathy, when standard surgical criteria are met in one thoracic aortic segment, extended prosthetic replacement may be considered in selected patients when physiologically and technically feasible.
Past Medical History and Family History
The patient had bronchial asthma under active treatment, with no history of cardiac surgery or a previously diagnosed connective tissue disorder. She had no history of smoking.
Her paternal grandmother and 5-year-old daughter had been diagnosed with aortic valve stenosis. Family members had not undergone genetic testing at the time of presentation; therefore, segregation analysis was not possible.
Differential Diagnosis
The differential diagnosis included heritable thoracic aortic diseases (HTADs) presenting with severe aortic regurgitation and ascending aortic aneurysm, such as FLNA-related aortopathy and other connective tissue disorders, as well as acquired degenerative aortopathy.
Investigations
Transthoracic echocardiography demonstrated severe aortic regurgitation. Preoperative transesophageal echocardiography confirmed severe aortic regurgitation attributable to right coronary cusp (RCC) bending, fenestration, and prolapse (Figure 1) and demonstrated reduced cusp height (RCC: 9.4 mm, left coronary cusp: 12.9 mm, noncoronary cusp: 13.2 mm), suggesting limited reparability. Chest computed tomography showed an ascending aortic aneurysm measuring 53 mm (aortic size index [ASI]: 3.91 cm/m2), with an aortic root diameter of 36 mm (ASI: 2.66 cm/m2) and a distal arch diameter of 31 mm (ASI: 2.29 cm/m2), as well as mild emphysematous changes. Pulmonary function testing revealed a severe mixed ventilatory defect (vital capacity: 73% of predicted; forced expiratory volume in 1 second of 1.20 L). Targeted genetic testing identified a pathogenic FLNA frameshift variant (c.3116_3119dup; p.Tyr1041AlafsTer3).
Figure 1.
Preoperative Transesophageal Echocardiography
Severe aortic regurgitation with an eccentric regurgitant jet directed toward the anterior mitral leaflet is demonstrated, attributable to bending, fenestration, and prolapse of the right coronary cusp.
Management
After optimization of asthma therapy, the patient underwent surgery. The ascending aorta measured >50 mm and showed prominent adventitial vasa vasorum; the root was mildly enlarged with a thin wall, whereas the ascending aortic wall appeared thickened (Figure 2). After cooling to 23 °C, circulatory arrest with selective antegrade cerebral perfusion via balloon-tipped cannulas to all 3 supra-aortic branches was instituted. Intraoperatively, the distal arch wall was found to be extremely thin, and to avoid leaving fragile native aortic tissue, the arch was transected just distal to the left subclavian origin, with division of the lesser curvature proximal to the ductus arteriosus. A 24-mm 4-branched Dacron arch graft was anastomosed to the distal arch using continuous 4-0 polypropylene with external felt reinforcement. Perfusion was then resumed via the graft side branch (circulatory arrest, 24 min), the 3 supra-aortic branches were sequentially anastomosed to the arch graft, and then cerebral perfusion was discontinued. A composite graft consisting of a 25-mm bovine pericardial bioprosthetic valve within a 28-mm Valsalva-type Dacron graft was sewn to the annulus with pledgeted 2-0 polyester noneverting mattress sutures, and both coronary arteries were reimplanted. The graft length was tailored, and the arch and root grafts were anastomosed end-to-end with running 4-0 polypropylene. Spontaneous sinus rhythm returned promptly after cross-clamp removal (cross-clamping time: 124 min), and the patient was weaned from cardiopulmonary bypass (total bypass time: 160 min).
Figure 2.
Intraoperative Findings
(A) The ascending aorta shows a maximal diameter of >50 mm with prominent adventitial vasa vasorum, whereas the aortic root wall is thin. (B) A fenestration of the right coronary cusp (arrow).
Outcome and Follow-Up
The patient was discharged home on day 8 without postoperative complications. At the 3-year follow-up, she remains asymptomatic, and transthoracic echocardiography and thoracoabdominal computed tomography have shown no significant abnormalities.
Pathology Correlation
The RCC showed hyaline degeneration and fibrosis with thickening of the cusp (Figure 3). Aortic wall specimens from 3 sites—the aortic root, ascending aorta, and distal arch—were submitted for histopathologic examination. In all specimens, the media showed diffuse disruption and thinning of elastic fibers with interlamellar deposition of Alcian blue–positive mucoid extracellular matrix. In the ascending aorta and distal arch, there was marked proliferation of adventitial vasa vasorum extending into the outer media, and in the distal arch, pronounced intimal fibrous thickening was also observed (Figure 4).
Figure 3.
Histopathology of the Aortic Valve (Right Coronary Cusp)
The right coronary cusp shows hyaline degeneration and fibrosis with thickening of the valve cusp. (A) Hematoxylin and eosin stain, ×40. (B) Hematoxylin and eosin stain, ×100.
Figure 4.
Histopathology of the Aortic Root, Ascending Aorta, and Distal Aortic Arch
(A and B) Aortic root (A, hematoxylin and eosin ×40; B, Elastica–van Gieson stain, ×100): The intima of the aortic root shows only minimal fibrous or atherosclerotic change, whereas the media shows marked disruption of the medial elastic fibers. (C and D) Ascending aorta (C, hematoxylin and eosin, ×40; D, Elastica–van Gieson stain, ×100): Prominent adventitial vasa vasorum are seen at the outer portion of the media, emanating from the adventitia (arrows), with minimal intimal fibrous thickening/atherosclerotic change. Diffuse fragmentation/attenuation of medial elastic fibers and deposition of Alcian blue–positive mucoid extracellular matrix within lamellar units is seen (inset: Alcian blue stain [pH 2.5], ×200). (E and F) Distal aortic arch (E, hematoxylin and eosin stain, ×40; F, Elastica–van Gieson stain, ×100): The intima (i in panel E) shows marked fibrous thickening. The media demonstrates disruption of elastic fibers with edema and accumulation of mucoid extracellular matrix between the elastic lamellae. Prominent adventitial vasa vasorum extending into the outer media were observed.
Discussion
FLNA pathogenic variants, classically associated with periventricular nodular heterotopia, are now recognized to cause a multisystem disorder involving connective tissue, skeletal, cardiovascular, and pulmonary manifestations.1, 2, 3 Recent cohort studies have shown that cardiovascular abnormalities and connective-tissue manifestations frequently coexist, and that thoracic aortic dilation or aneurysm occurs in a substantial proportion of patients harboring FLNA loss-of-function variants.3,4 In the largest series to date, aortic aneurysm or dilation was identified in 18% of genetically confirmed cases, whereas in a cohort selectively enriched for cardiovascular and connective-tissue features, approximately three-fourths of patients exhibited aortic involvement.3,4 Collectively, these observations support the classification of FLNA-related disease as an HTAD requiring lifelong cardiovascular surveillance.3, 4, 5
However, in contrast to other genetically mediated aortic diseases such as Marfan syndrome, Ehlers-Danlos syndrome, and Loeys-Dietz syndrome, evidence regarding FLNA-related aortopathy remains limited, and the risks of rupture and dissection remain poorly defined. Consequently, the 2022 American College of Cardiology/American Heart Association guidelines do not provide gene-specific diameter thresholds for surgical intervention in FLNA-related aortic disease.5,6 Although surgical thresholds for HTAD vary according to the underlying gene and syndrome, current guidelines generally advocate prophylactic surgery at lower diameters than for sporadic aneurysms, often in the range of ≤5.0 cm in the ascending aorta.5,6 In the present case, an ascending aortic aneurysm measuring 53 mm in a young patient with FLNA-related aortopathy was considered an indication for surgery.
Existing FLNA cohorts and case reports suggest that this gene confers a non-negligible risk of adverse aortic events.1, 2, 3, 4,7,8 In a series reported by Chen et al,4 thoracic aortic aneurysm was the only documented cause of nontraumatic premature death, and 2 adults—a 36-year-old man and a 41-year-old woman—died of spontaneous aortic rupture at diameters below the recommended surgical thresholds for other heritable aortopathies; in one of these patients, the aortic diameter increased from 32 to 42 mm between ages 36 and 41 before sudden death, with autopsy confirming rupture. Progressive enlargement of residual aortic segments after ascending aorta replacement has also been reported. Although the number of documented cases remains small, these findings are consistent with experience in other heritable aortopathies, in which dissection or rupture may occur at relatively modest aortic diameters. Collectively, these observations raise concern regarding both the timing of intervention and the extent of residual native aorta in FLNA-related disease.5,6
In this context, and given the patient's young age and desire for future pregnancy, extended replacement was undertaken to minimize the length of potentially vulnerable native aorta. Histopathologic examination revealed advanced medial degeneration, with disruption of elastic fibers in the aortic root and arch despite their diameters being within the normal range, suggesting that disease involvement extended to aortic segments that appeared macroscopically normal. These findings may therefore provide additional pathologic support for the appropriateness of our strategy of replacing, with prosthetic grafts, a broader extent of diseased aorta. Histopathologic examination of the aortic valve demonstrated severe degeneration of the RCC, characterized by hyaline change, fibrosis, and leaflet thickening, thereby supporting the appropriateness of aortic valve replacement rather than a valve-sparing approach. Accordingly, a bioprosthetic valve was selected to accommodate future pregnancy.
Conversely, our experience should be interpreted with caution. This report describes a single case, and extended replacement involving both the aortic root and arch carries greater operative risk than isolated ascending aortic replacement. Moreover, the histopathologic specimens we examined represent only a portion of the aortic wall and do not demonstrate that similar abnormalities are present throughout; thus, they cannot by themselves be used to generalize our approach to more extensive replacement.
Therefore, the timing and extent of aortic replacement in FLNA-related aortopathy should be individualized, based on an integrated assessment of aortic diameter and growth rate, coexisting valvular disease and heart failure, and institutional expertise. Prospective registries of patients with FLNA variants, incorporating systematic imaging follow-up, are needed to clarify gene-specific risk profiles and to determine whether more aggressive prophylactic and extended repair strategies translate into improved long-term outcomes. Taken together, this case provides histopathologic evidence of pan-aortic involvement in FLNA-related aortopathy and illustrates a rationale for considering extended root and arch replacement once standard surgical criteria are met in any thoracic aortic segment.
Conclusions
In FLNA-related aortopathy, when a pathogenic variant is known and one thoracic aortic segment already fulfills standard surgical indications, it may be reasonable to consider extending graft replacement to contiguous, normal-diameter segments such as the root or arch, provided the additional extent is technically and physiologically acceptable. Valve replacement may be necessary when cusp degeneration and reduced cusp height preclude durable repair.
Funding Support and Author Disclosures
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Equipment List.
Implants
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ePTFE = expanded polytetrafluoroethylene.
Patient Consent and Ethics Statement
Written informed consent for publication was obtained. The study protocol was approved by the Research Ethics Committee of the Faculty of Medicine, Juntendo University (JHS25-028; November 5, 2025).
Footnotes
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
References
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